Bioenergetics I PT 8202 2025 PDF

Bioenergetics I D O N A L M U R RAY , P H D , C S C S PT 8202 Big Picture Concepts 1. All systems are always on 2. Homeostasis and allostasis 3. Supply and demand 4. Location of energy breakdown and synthesis 5. Number of reactions – yield from reactions Plant Kingdom Animal Kingdom Introductio...

Bioenergetics I D O N A L M U R RAY , P H D , C S C S PT 8202 Big Picture Concepts 1. All systems are always on 2. Homeostasis and allostasis 3. Supply and demand 4. Location of energy breakdown and synthesis 5. Number of reactions – yield from reactions Plant Kingdom Animal Kingdom Introduction Metabolism: sum of all chemical reactions that occur in the body Anabolic reactions Synthesis of molecules Catabolic reactions Breakdown of molecules Bioenergetics Converting foodstuffs (fats, proteins, carbohydrates) into energy Involves the transformation of chemical energy (glucose, glycogen, FFA, amino acids) into mechanical energy (work) Bioenergetics In humans metabolic reactions results in free energy used for work & heat release Hard to measure each separately Almost lump both together Heat + work eventually results in heat production This heat production is measured as a kilocalorie (kcal) Amount of heat required to raise 1kg of water 1 C° Bioenergetics The rate of energy production is controlled by the amount of available substrate Along with enzyme activity – rate limiting enzyme Metabolic pathways involve multiple reactions each catalyzed by an enzyme Each system or pathway has specific enzymes that turn on or activate the entire pathway Rate limiting enzymes essentially control the entire biochemical pathway Guyton and Hall, 14th Ed, Bioenergetics Skeletal muscle has sensitive controls that cause different metabolic pathways to run depending on ATP demand ATP-PCR Glycolysis Oxidative phosphorylation ATP supplied to body through these pathways – different intensity demands will cause upregulation of one pathway But remember all pathways are working at the same time Metabolic pathways occur at two levels Substrate level Phosphorylation anaerobic metabolism immediate energy systems glycolytic system (anaerobic or fast glycolysis) Oxidative level Phosphorylation aerobic metabolism oxidation of glucose beta oxidation protein catabolism and gluconeogenesis The goal of all of these energy systems is to replenish ATP to provide energy for cellular processes https://www.fsps.muni.cz/emuni/data/ reader/book-6/05.html Adenosine Triphosphate (ATP) A high energy molecule found universally in living systems Energy-carrying molecule that serves as the source of energy at the cellular level; provides energy to drive processes of living cells Performs essential function of storing energy for various cellular activities Only source the human body can use to do work Impaired ATP production can increase fatigue and reduce human performance  ATP ATP + H 2 0 ATPASE ADP + P I + H + = -7.3KCAL/MOL ATP The enzyme ATPase is vital for this reaction It catalyzes the hydrolysis – splits/breaks using a molecule of water Once ATP is broken down you are left with ADP Inorganic Phosphate Hydrogen ion – more on this later Energy – roughly 7.3kcal worth The reaction can and does go in both directions Needs 7.3 kcal worth of energy to create new ATP ATP ATP is continually being resynthesized using both oxidative and non-oxidative rxns Intracellular ATP concentration is kept low 80-100 grams available at any one time Reduction in [ATP] and subsequent increase in [ADP] stimulates metabolic processes responsible for ATP to be resynthesized Guyton and Hall, 14th Ed, Oxidation-Reduction Reactions All about the transfer of electrons Oxidation: removing an electron – transfers/loses Reduction: addition of an electron - gains Oxidation and reduction are always coupled reactions In cells, often involve the transfer of hydrogen atoms rather than free electrons Hydrogen atom contains one electron & one proton A molecule that loses a hydrogen also loses an electron and, therefore, is oxidized Oxidation-Reduction Reactions Nicotinomide adenine dinucleotide (NAD) Flavin adenine dinucleotide (FAD) NAD + 2H+ NADH + H+ FAD + 2H+ FADH2 Main Nutrients for Energy Metabolism Carbohydrates – stored glycogen, blood glucose Fats – stored lipids Protein - during intense long duration exercise, prolonged fasting Under resting conditions ATP mainly produced through breakdown of fats and carbs Intensity goes up this changes Carbohydrates Made up of a combination of carbon, hydrogen and oxygen atoms Main fuel source in the body Approx 4kcal of energy per g when catabolized Carbs we eat enters blood stream as a 6-carbon glucose molecule Entry into metabolism for ATP synthesis Storage in cell cytoplasm as glycogen – 2,000 kcal in muscle, 500 kcal in liver Macronutrient classified into 3 main categories Monosaccharides Oligosaccharides Complex Sugar: Polysaccharides: Starches Carbohydrates - Monosaccharides C6H12O6 Glucose- the primary fuel source during exercise and physical activity – roughly 80% fructose - fructose degradation occurs primarily in the liver glycogen - stored form of glucose – generally in the liver and muscle Lipids - Fats Same atoms as carbs just differ in molecular structure Fats are insoluble meaning they do not attract water when stored So higher level of potential energy stores of fat Doesn’t have the added weight of water Fat catabolism allows for way more energy per g than carbs about 9 kcal/g a lot more stored energy as well – roughly 75,000 kcal for a 65 kg male Lots of different types of lipids Fatty acids Triacylglycerols Phospholipids - not really used in energy metabolism Steroids – not really used in energy metabolism Fatty acids Made up of log chain carbons each bound by hydrogen and a carboxyl group at one end Saturated fatty acids – single bonds between each of the carbons Unsaturated – double bond Examples for energy production Palmitic acid More on this later!! Protein Molecular makeup includes nitrogen Made up of a bunch of different amino acids Energy yield is very small – 4 kcal/g Not really used for energy metabolism, only as last resort If used for energy then nitrogen needs to be removed Once nitrogen is removed Converted to glucose Converted to fatty acid Or carbon skeleton of amino acid enters the energy pathway Energy substrates for metabolism Energetics of Human Movement Overlapping energy systems allow participation in a wide variety of activities Power Speed Endurance Three distinctly different energy systems produce ATP over the range of activity durations and intensities Reliance on power and speed systems can limit daily human function Energy Systems Overview Immediate Energy Systems (Phosphagen System) ATP Phosphocreatine Adenylate Kinase (myokinase) rxn Non-oxidative Energy Systems ( Fast Glycolysis) Glucose Glycogen Oxidative Energy Systems (Oxidative Phosphorylation) Glucose Slow Glycolysis Glycogen Fatty acids Amino Acids  Immediate Energy Systems Adenylate Kinase (myokinase) rxn https://europepmc.org/article/MED/19196246 Immediate Energy System Stored ATP Immediate energy for ~2 sec. Enzyme – ATPase Phosphocreatine Another high energy phosphate Re-phosphorylates ATP Enzyme – creatine kinase ~5 times greater [PCr] in the cell Immediate energy for 10 seconds ADP + CrP + H+ ~ {CK} Energy shuttle - mitochondrial creatineATP+Cr kinase Benefits/Liabilities of ATP-PCr System Represents most rapidly available source of ATP Does not depend on long series of chemical reactions – only one ATP/PCr stores can be enhanced through training The amount of energy available is the most limited of all systems; can only fuel all out efforts to approx 10-14 sec PCr requires roughly 10.3 kcal of energy input for synthesis Training increases [PCr] Increase creatine kinase activity by as much as 35% - 5 s sprint interval training Can take up 3 minutes to be fully replenished https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0838.1997.tb00141.x https://pubmed.ncbi.nlm.nih.gov/17991697/ Glycolysis/Glycogenolysis Glycolysis is the process of getting energy from the 6-carbon glucose molecule Break it down to create ATP Glucose 6-phosphate comes from; Blood glucose Glycogen – liver and muscles Glycogen to glucose 6-phosphate is called glycogenolysis Plasma glucose to glucose 6-phosphate requires ATP breakdown to occur Goal of metabolism is to meet the demand for ATP – can do this with or without O2 Only pathway that can do both  Blood glucose entry Glut-4 receptors migrate to sarcolemma bind glucose Glut-4 receptors become glucose transporters when stimulated by either insulin or exercise During exercise, stimulation of transport is additive according to exercise intensity and is independent of insulin concentration Nonaerobic glycolysis/glycogenolysis Occurs in the cytosol of the muscle cell Both molecules (glucose or glycogen) enter the pathway as glucose 6-phosphate and yield; Two pyruvate – further reduced to lactate Two or three ATP H2O Two NADH Glucose enter pathway via blood glucose and is converted to glucose 6-phosphate through hexokinase reaction Fast vs Slow Glycolysis Originally described as “anaerobic” and “aerobic” glycolysis More accurate description is “fast” and “slow” glycolysis The net result of glycolysis (pyruvate vs lactate) has little to do with O2 availability: instead has more to do with relative glycolytic & mitochondrial activities Fast vs slow is determined by energetic demand (ie demand for ATP) https://www.fsps.muni.cz/emuni/data/reader/book- 6/05.html Glycogen – glycogenolysis Must be first broken down to glucose 1-phosphate The rate limiting enzyme here is phosphorylase Glycogenolysis is more active during higher activity levels Advantages as it doesn’t use up any ATP Ready for glycolysis now!! Both blood glucose and glycogen have been broken down to glucose 6-phosphate Nine/10 steps can be divided into two phases Phase I Steps 1-4 results in two isomers of substrate requires an input of two ATPs *if from glucose Phase II Steps 5-9/10 produces pyruvate, ATP and NADH Glucose to G6-P – enzyme hexokinase Step 3 ATP lost – phosphofructokina se Committed step Step 6 NAD reduced to NADH – Step 7 ATP goes to ETC produced Final step – ATP & pyruvate produced Rate limiting enzymes Hexokinase – simple glucose to Glucose 6- phosphate Phosphofructokinase – step 3 Glyceraldehyde phosphate dehydrogenase – Step 5 Phosphoglycerate kinase – step 6 Pyruvate kinase – final step to create pyruvate Byproducts of glycolysis Three important products Pyruvate that can be converted to lactate or further used in oxidation ATP produced as a by-product – Net gain = glucose (2 ATP) = glycogen (3 ATP) NAD (nicotinamide adenine dinucleotide) reduced (gain electrons, H+) to NADH – net gain 2 NADH Fate of H from glycolysis + Aerobic metabolism: NAD reduced to NADH+ and shuttles this H+ to the ETC producing 3 ATP per NADH+ (2 ATP per FADH+) Anaerobic metabolism: Pyruvate remains in cytosol, converted to Lactate which produces H+ that must be buffered by the bicarbonate buffering system Bases for the concept of the anaerobic threshold Lactate – the worst thing in the human body What is Lactate? Essentially just broken down glucose A helpful intermediate when need for ATP is very high It is not what is causing you pain It does not cause pH to change too much It is actually a good thing Otto Meyerhof Father of glycolysis Meyerhof determined that glycogen is converted to lactate in the absence of oxygen and showed that in the presence of oxygen the rest is converted back to glycogen Energy is derived from sugar – glucose One of the first to say lactate build up was associated with fatigue Won Noble Prize in 1922 Others noticed that race horses after intense gallop and were extremely tired had build of lactate in the system – correlation not causation! Clear correlation between lactate build up and pH of the muscle Muscle acidosis does occur especially during high level exercise Blamed for pain associate with exercise – not the case Blamed for DOMS – not the case How many coaches, TV pundits, commentators have you heard say that lactate is building Step 6 of glycolysis is what really matters NAD is a substrate that accepts an electron and a proton (H+) meaning it is reduced to NADH2 Very important step in glycolysis, lactate formation and electron transport chain Lactate When demand for ATP is low things run smoothly No issue with O2 delivery NADH + H+ are dealt with – oxidized Pyruvate transported into the mitochondria and gets transformed to Acetly-CoA via pyruvate dehydrogenase (PDH) – more ATP produced Or NADH directly dealt with Allowing for NAD recylcing NADH shuttle Low levels of activity where ATP demand is not high NADH and H+ produced during step 6 are shuttled elsewhere NADH can’t easily pass through the inner-mitochondrial membrane Needs a pathway or a shuttle Two main ones Aspartate/Malate Glycerol/phosphate Oxaloacetate in the cytosol is reduced to malate Uses the NADH from glycolysis as the electron (H+) donor Carried then into matrix of mitochondria via malate NAD is the reduced to form NADH from the malate and goes into Krebs cycle Lactate Demand for ATP goes up as intensity of activity goes up Glycolytic rate increases The shuttles can’t keep up with the production of NADH in the cytosol Failure of the mitochondrial hydrogen shuttle to keep pace with glycolysis Excess NADH favors conversion of pyruvate to lactate  Lactate In times of excess H+ the ion is cleaved from NADH+ and added to pyruvate to form lactate The enzyme required for this reaction is lactate dehydrogenase (LDH) If lactate was not formed, activity would have to be stopped due to a large drop in intracellular pH Thus, while lactate may be a marker for fatigue, it serves to buffer H+ Goes through two shuttles into mitochondria Demand increasing Can’t be oxidized Builds up Lactate Without the regeneration NAD glycolysis would slow down hugely At rest skeletal muscle lactate levels are around 1 mmol/kg Can get as high as 20 mmol/kg during max exercise Lactate generation allows for glycolysis to continue and for ATP production to stay at high rate Lactate is not waste It is a vital molecule that can support metabolic flux – referred to as dumping ground! Lactate concentration balance affects human performance Lactate shuttled Once lactate has been formed it needs to be dealt with NOT very efficient to convert lactate back into pyruvate in the cytosol as it needs NAD Remember NAD needed for glycolysis Skeletal muscle lactate then moved or shuttled into the mitochondria or blood stream via monocarboxylate transporters Monocarboxylate transporters (MCTs) Monocarboxylate transporters facilitated diffusion transport of lactate and pyruvate in and out of cells located on plasma and mitochondrial membrane reversible transporter involves H+ transport MCT1 and MCT4 are major MCT isoforms MCT1 found more in oxidative fibers MCT4 found more in glycolytic fibers at least 8 isoforms of MCTs known in humans Lactate removal Lactate that has buffered H+ also shuttled out of the cell for use elsewhere – again done through MCTs Blood Liver Skeletal muscle Can use the accumulation of blood lactate as a marker of intensity Buffering in blood Lactate enters blood Could cause a huge decrease in blood pH if one cannot buffer the lactate and H+ Bicarbonate system plays vital role here H+ + lactate- + Na+ + HCO3- Na+ + H2CO3  H2O + CO2 Lactate Utilization Lactate is an important fuel during exercise. Muscles can utilize lactate in 3 ways: Lactate produced in the cytoplasm can be taken up by the mitochondria of the same muscle fiber and oxidized. Lactate can be transported via MCT transporters to another cell and oxidized there (lactate shuttle). Lactate can recirculate back to the liver, reconverted to pyruvate and then to glucose through gluconeogenesis. Metabolic Fate of Lactate During exercise: ~75% oxidized by heart, liver, and ST fibers During recovery: oxidized by heart, ST fibers, and liver converted to glycogen incorporated into amino acids La metabolism depends on metabolic state Lactate Shuttle Cori Cycle Anaerobic Energy Expenditure: Lactate Threshold Lactate threshold: point at which blood lactate accumulation  markedly Lactate production rate > lactate clearance rate Interaction of aerobic and anaerobic systems Good indicator of potential for endurance exercise Usually expressed as percentage of V O2max Mechanisms for lactate threshold Low muscle oxygen – debatable or not really the cause Accelerated glycolysis Recruitment of fast-twitch muscle fibers Reduced rate of lactate removal from the blood Practical uses in prediction of performance and as a marker of exercise intensity “Creatine increases the resynthesize process of Pcr and suppresses H⁺ formation, the cause of fatigue induction in the process of ATP production, and helps increase exercise performance as an acidifying buffer in the active muscle during exercise” Next Week…. Finish off bioenergetics oxidative phosphorylation ATP production from fats How all this relates to exercise and performance